Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases

Hanjie Jiang, Stefani N. Thomas, Zan Chen, Claire Y. Chiang, Philip A. Cole

Research output: Contribution to journalArticle

Abstract

NEDD4-1 E3 ubiquitin protein ligase (NEDD4-1) and WW domain-containing E3 ubiquitin ligase (WWP2) are HECT family ubiquitin E3 ligases. They catalyze Lys ubiquitination of themselves and other proteins and are important in cell growth and differentiation. Regulation of NEDD4-1 and WWP2 catalytic activities is important for controlling cellular protein homeostasis, and their dysregulation may lead to cancer and other diseases. Previous work has implicated noncatalytic regions, including the C2 domain and/or WW domain linkers in NEDD4-1 and WWP2, in contributing to autoinhibition of the catalytic HECT domains by intramolecular interactions. Here, we explored the molecular mechanisms of these NEDD4-1 and WWP2 regulatory regions and their interplay with allosteric binding proteins such as Nedd4 family-interacting protein (NDFIP1), engineered ubiquitin variants, and linker phosphomimics. We found that in addition to influencing catalytic activities, the WW domain linker regions in NEDD4-1 and WWP2 can impact product distribution, including the degree of polyubiquitination and Lys-48 versus Lys-63 linkages. We show that allosteric activation by NDFIP1 or engineered ubiquitin variants is largely mediated by relief of WW domain linker autoinhibition. WWP2-mediated ubiquitination of WW domainbinding protein 2 (WBP2), phosphatase and tensin homolog (PTEN), and p62 proteins by WWP2 suggests that substrate ubiquitination can also be influenced by WW linker autoinhibition, although to differing extents. Overall, our results provide a deeper understanding of the intricate and multifaceted set of regulatory mechanisms in the control of NEDD4-1-related ubiquitin ligases.

Original languageEnglish (US)
Pages (from-to)17421-17436
Number of pages16
JournalJournal of Biological Chemistry
Volume294
Issue number46
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

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Ligases
Ubiquitin
Ubiquitin-Protein Ligases
Ubiquitination
Catalyst activity
Proteins
Protein Phosphatase 2
Nucleic Acid Regulatory Sequences
Cell growth
Cell Differentiation
Catalytic Domain
Carrier Proteins
Homeostasis
Chemical activation
Substrates
Growth
Neoplasms

PubMed: MeSH publication types

  • Journal Article

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Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases. / Jiang, Hanjie; Thomas, Stefani N.; Chen, Zan; Chiang, Claire Y.; Cole, Philip A.

In: Journal of Biological Chemistry, Vol. 294, No. 46, 01.01.2019, p. 17421-17436.

Research output: Contribution to journalArticle

Jiang, Hanjie ; Thomas, Stefani N. ; Chen, Zan ; Chiang, Claire Y. ; Cole, Philip A. / Comparative analysis of the catalytic regulation of NEDD4-1 and WWP2 ubiquitin ligases. In: Journal of Biological Chemistry. 2019 ; Vol. 294, No. 46. pp. 17421-17436.
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